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A Phase 1-2, Multicenter, Open-Label Study of The X-Linked Inhibitor of Apoptosis (XIAP) Antisense AEG35156 Given in Combination With Gemcitabine in Patients With Advanced Pancreatic Cancer

Phase 1/Phase 2
18 Years
Not Enrolling
Carcinoma, Pancreas

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Trial Information

A Phase 1-2, Multicenter, Open-Label Study of The X-Linked Inhibitor of Apoptosis (XIAP) Antisense AEG35156 Given in Combination With Gemcitabine in Patients With Advanced Pancreatic Cancer

Apoptotic induction in cancer cells is a sought after therapeutic goal. Most successful
anticancer agents activate apoptosis pathways in the cancers they treat. Apoptotic pathways
in cells appear to converge on a single family of enzymes, the caspases, which are proteases
that dismantle the cell in an orderly, non-inflammatory fashion, resulting in cell death.
The X-linked Inhibitor of Apoptosis (XIAP) is the only known cellular inhibitor of caspases,
its over expression thereby blocks the principal means of apoptosis. A wide range of
evidence indicates that cellular overexpression of members of the IAP family is a
fundamental means by which many cancer cells evade death, even in the presence of strong
extrinsic (death receptor-mediated) and intrinsic (mitochondria-mediated) apoptotic cues.
The inhibition of cellular XIAP activity, specifically in cancer cells under stress and
primed for apoptosis by chemotherapeutic agents, is viewed as a powerful means of tipping
the balance towards cell death. In particular, XIAP has been shown to be overexpressed in
pancreatic cancer and to play an important role in gemcitabine resistance. AEG35156 is a
second generation antisense which targets XIAP mRNA to lower XIAP levels and the apoptotic
threshold of cancer cells, enhancing their sensitivity to intrinsic death and chemotherapy.
AEG35156 may thus enhance the anticancer activity of gemcitabine in patients with advanced
pancreatic cancer.

Inclusion Criteria:

- Patients with histologically or cytologically confirmed advanced pancreatic
adenocarcinoma who are candidates for first-line gemcitabine therapy

- Karnofsky performance >70%

- One or more metastatic tumors measurable by RECIST criteria on CT scan or MRI (Phase
2 part only)

- Life expectancy of at least 3 months

- Age > 18 years

- Signed, written IRB-approved informed consent

- A negative serum pregnancy test (if applicable)

- Acceptable liver function:

- Bilirubin < 1.5 times the institution's upper limit of normal

- AST (SGOT), ALT (SGPT) and Alkaline phosphatase < 2.5 times the institution's upper
limit of normal

- Acceptable renal function:

- Serum creatinine within normal limits, OR calculated creatinine clearance > 60
mL/min/1.73 m2 for patients with creatinine levels above institutional normal

- Acceptable hematologic status:

- Granulocyte > 1500 cells/uL

- Platelet count > 100,000 plt/uL

- Hemoglobin > 9.0 g/dL

- Acceptable coagulation status:

- PT within normal limits

- PTT within normal limits

- For women of child-producing potential, the use of effective contraceptive methods
during the study

- Prior radiotherapy for local disease is allowed provided disease progression has been
documented, and treatment completed at least 4 weeks prior to registration

Exclusion Criteria:

- Prior chemotherapy for pancreatic cancer, except for 5-fluorouracil or gemcitabine
given as a radiosensitizer

- Active progressive brain metastases including the presence of any related symptoms or
need for corticosteroids. A CT or MRI scan of the head is necessary in patients with
a history of brain metastases to document the stability of prior lesions.

- Known bleeding diathesis or concurrent treatment with anticoagulants except patients
on non-therapeutic line maintenance coumadin

- Pregnant or nursing women. NOTE: Women of child-bearing potential must agree to use
adequate contraception (sterile or surgically sterile; hormonal or barrier method of
birth control; or abstinence) prior to study entry and for the duration of study
participation. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately

- Men who are unwilling to use acceptable forms of birth control when engaging in
sexual contact with women of child bearing potential

- Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic

- Known infection with HIV, hepatitis B, or hepatitis C

- Serious nonmalignant disease that could compromise protocol objectives in the opinion
of the investigator and/or the sponsor

- Patients who are currently receiving any other investigational agent. Subjects who
have used a previous antisense oligonucleotide in the last 90 days will be excluded

- Unwillingness or inability to comply with procedures required in this protocol

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the recommended dose of AEG35156 when used in combination with gemcitabine and the change in response rate of gemcitabine in patients

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Daniel D Von Hoff, MD, FACP

Investigator Role:

Principal Investigator

Investigator Affiliation:

TGen Clinical Research Services at Scottsdale Healthcare


United States: Food and Drug Administration

Study ID:




Start Date:

September 2007

Completion Date:

November 2009

Related Keywords:

  • Carcinoma
  • Pancreas
  • Pancreatic
  • antisense
  • oligonucleotide
  • gemcitabine
  • Carcinoma
  • Pancreatic Neoplasms



Gabrail Cancer CenterCanton, Ohio  44718
Scottsdale Healthcare - SheaScottsdale, Arizona  85260
Mayo Clinic ArizonaScottsdale, Arizona  85259
Arizona Cancer Center - University of ArizonaTucson, Arizona  85724